Selective and sustained pulmonary vasodilation with inhalational nitric oxide therapy in a child with idiopathic pulmonary hypertension

Clinical and laboratory observations Selective and sustained pulmonary vasodilation with inhalational nitric oxide therapy in a child with idiopathic pulmonary hypertension John P. Kinsella, MD, Warren H. Toews, MD, D e s m o n d Henry, MD, a n d S t e v e n H. A b m a n , MD From the Department of Pediatrics, Children's Hospital and the Universityof Colorado School of Medicine, Denver

Low doses of inhaled nitric oxide caused selective and sustained pulmonary vasodilation in an infant with pulmonary hypertension without causing systemic hypotension, despite the failure of treatment with other vasodilators. (J PEDIAI'R 4993;422:803-6) Although some success in the pharmacologic management of severe pulmonary hypertension has been reported, I, 2 vasodilator therapy is often unsuccessful in lowering or sustaining a decline in pulmonary vascular resistance because of concomitant systemic hypotension, cardiac arrhythmias, diminished responsiveness to many agonists, or tachyphylaxis.3 Recently Pepke-Zaba et al. 4 reported that inhaled nitric oxide caused potent and selective pulmonary vasodilation in adults with severe primary pulmonary hypertension; however, treatment with NO was brief (10 minutes). Recent studies in newborn infants with severe persistent pulmonary hypertension showed that brief exposure to inhalational NO (80 ppm for 30 minutes) increased postductal arterial oxygen saturation,5 and low-dose inhalational NO therapy (6 ppm for 24 hours) caused sustained improvement in oxygenation in newborn infants with severe PPHN, leading to resolution of PPHN and complete recovery.6 The effects of

We are grateful for the support of the respiratory therapy department and the nursing staff of the pediatric intensive care unit, Children's Hospital, Denver. Supported in part by grants from the National Institutes of Health (H L-01932; ttL-41012; HL-46481). Submitted for publication Nov. 14, 1992; accepted Dec. 28, 1992. Reprint requests: John P. Kinsella, MD, Divisionof Neonatology, Box B-070, Children's Hospital, 1056 E. 19th Ave., Denver, CO 80218-1088. Copyright 9 1993 by Mosby-Year Book, Inc. 0022-3476/93/$1.00 + .10 9/26/45226

low-dose inhalational NO therapy in older infants with pulmonary hypertension are unknown. We report the case of an infant with severe unexplained pulmonary hypertension in whom standard pharmacologic agents (isoproterenol, prostaglandin El, tolazoline, and nifedipine) caused systemic hypotension, whereas inhaled NO at low concentrations caused selective and sustained pulmonary vasodilation. See related article, p. 743.

NO PPHN PVR

Nitric oxide I Persistent pulmonary hypertension of the newborn Pulmonary vascular resistance

CASE REPORT A 5-month-old white girl was well until the day of admission, when severe respiratory distress and cyanosisdeveloped. Although at birth she had been small for her gestational age of 32 weeks, she had an uneventful newborn course. She had no evidenceof perinatal stress or cardioputmonary disease and required no mechanical ventilation or supplemental oxygen. Aftgr discharge, no clinical problems were found by her pediatrician. On the day of admission, the patient became tachypneic and dusky without an apparent precipitating event. Her respiratory distress progressed for several hours. When she arrived in the emergency department, an endotraeheal tube was immediately placed and her lungs were ventilated. Arterial blood tensions after

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T a b l e . Cardiac catheterization results for baseline, 20 ppm N O , and 40 ppm N O inhalation

Study period Baseline NO, 20 ppm NO, 40 ppm

o/APo2 ratio

Pvo2 (mm Hg)

PVR (ram Hg/L/mln/m 2)

SVR (mm Hg/L/min/m 2)

PVR/SVR ralio

el (L/min/m 2)

0.138 0.171 0.175

47 67 67

! 8.01 11.11 8.11

21.32 18.27 16.67

0.84 0.61 0.49

3.33 4.05 4.44

a/APoz, Ratio of arterial to alveolar partial pressure of oxygen; Pro2, mixed venous partial pressure of oxygen;SVR, systemic vascular resistance; CI, cardiac index.

intubation (fraction of inspired oxygen 1.00) revealed ptl 6.88, arterial carbon dioxide tension 35 mm ttg, arterial oxygen tension 108 mm ttg, and base deficit 27 mEq/L. Diminished femoral pulses suggested a possible ductus-dependent obstructive cardiovascular lesion. Administration of prostaglandin El (0.13 t~g/kg per minute) failed to provide clinical improvement and decreased systemic arterial blood pressure. A radiograph of the chest demonstrated cardiomegaly with mild pulmonary edema. Echocardiography revealed a markedly dilated and hypertrophied right ventricle with right-to-left shunting across a patent foramen ovale and rightward deviation of the ventricular septum, consistent with severe pulmonary hypertension. No anatomic cardiovascular lesions were found. The patient was transferred to the Children's tlospital, Denver, Colo., for further evaluation and management. After admission, attempts were made to reduce PVR by using hyperventilation (with sedation and pharmacologic paralysis), hyperoxia, and sodium bicarbonate infusion. Despite these therapies, echocardiographic signs of severe pulmonary hypertension persisted, and the patient had intermittent episodes of cyanosis, bradycardia, and hypotension. Therapy with tolazoline, 0.5 to 1.0 mg/kg per hour, was started 15 hours after admission but was discontinued because of marked systemic hypotension. Because of the severity of pulmonary hypertension and the lack of clinical response to pharmacologic vasodilators, a trial of NO inhalation was started after extensive discussions with the family. Inhalation of NO, 20 ppm, abruptly improved oxygenation (ratio of arterial to alveolar partial pressure of oxygen increased from 0.119 to 0.302) without a change in systemic arterial pressure. Clinical improvement was sustained during inhalation of NO, allowing for the discontinuation of other vasoactive agonists (isoproterenol, dopamine). After 20 hours of NO treatment with a stable clinical course, cardiac catheterization was performed to quantitate the severity of pulmonary hypertension, to assess the hemodynamic effects of inhaled NO, and to rule out an anatomic cardiovascular lesion. Inhalation of NO was briefly discontinued during transport to the catheterization laboratory and was restarted after baseline hemodynamic measurements were recorded. During cardiac catheterization, inhaled NO at 20 and 40 ppm for 10 minutes reduced PVR by 38% and 55%, respectively (Table). Systemic vascular resistance fell slightly during NO treatment, but the ratio of pulmonary to systemic vascular resistance decreased by 42% at 40 ppm of inhaled NO. After cardiac catheterization, pulmonary artery pressure was continuously monitored in the pediatric intensive care unit. A concentration of NO as low as 6 ppm caused sustained reductions in pulmonary artery pressure for the entire 45-hour treatment period. Methemoglobin levels remained less than 2% throughout the

treatment period. Several attempts were made to stop NO treatment, but pulmonary artery pressure quickly increased toward systemic levels. In an attempt to substitute long-term therapy for inhalational NO, sublingual nifedipine, 0.3 mg/kg, was given. Although mean pulmonarY artery pressure decreased by 29%, marked systemic hypotension also occurred (Figure). Because of the experimental nature of NO treatment and the lack of a suitable alternative to long-term therapy, the parents requested that "heroic" treatments be withdrawn; the patient died shortly after termination of the NO inhalations. Postmortem examination confirmed that the heart and pulmonary veins were structurally normal. Although detailed morphometric studies were not performed, histologic studies of the lung demonstrated marked medial hypertrophy of preacinar and intraacinar arteries. There were no signs of plexogenie arteriopathy, veno-occlusive disease, or thromboembolism. Results of routine viral and bacterial cultures were negative. No apparent cause for this child's pulmonary hypertension was identified. DISCUSSION The potential utility of inhaled N O in the treatment of pulmonary hypertension was first suggested by Pepke-Zaba et al. 4 In adults with primary pulmonary hypertension, inhaled N O selectively decreased PVR, whereas prostacyclin caused a moderate fall in systemic vascular resistance as well. These observations were limited, only a single and relatively high dose of N O (40 ppm) was studied, and the treatment period was only 10 minutes. Similar limitations apply to the study by Roberts et al. 5 in newborn infants. However, we have dcmonstrated that extending the duration of exposure to low doses of inhalational N O caused sustained improvement in oxygenation leading to complete relief of scvere P P H N . 6 Our patient provides a clinical example of the ability of inhaled N O to selectively lower pulmonary artery pressure when other pharmacologic agents have failed. In addition, this report extends the previous study by demonstrating the ability of inhaled N O to sustain prolonged decreases in pulmonary artery pressure (in addition to improvements in oxygenation) at low concentrations (6 ppm) in a patient beyond the newborn period. Numerous studies have suggested the potential role of various vasodilators in the treatment of pulmonary hypertension, 1"3 but the effectiveness of these agents is often limited by adverse effects such as systemic hypotension. 3

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Kinsella et al.

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Time (minutes) F i g u r e . Percentage of change in mean pulmonary (lower pane/) and systemic (upper panel) arterial pressures with sublingual nifedipine therapy (dark boxes) versus inhaled NO ( 14 ppm; clear boxes). Equivalent reductions in pulmonary artery pressure were achieved with both agents, but nifedipine caused a marked fall in systemic blood pressure.

Inhaled NO appears to be unique in its ability to lower PVR selectively and improve gas exchange. Mechanisms underlying its "selective" response include the rapid diffusion of NO across alveolar barriers into vascular smooth muscle ceils, stimulating guanylate cyclase activity, increasing the cyclic guanosine monophosphate concentration, and causing vasodilation.4, 7-10 Because NO rapidly and avidly binds hemoglobin, it is rapidly inactivated, limiting its ability to cause systemic hypotension. In addition, inhaled NO preferentially travels to better-ventilated lung units, thereby optimizing ventilation-perfusion matching and reducing intrapulmonary shunting. Several animal studies have demonstrated the efficacy of inhaled NO in lowering PVR selectively in adult animals during acute hypoxia and pharmacologically induced pulmonary hypertension, 9, lo and in the immature (fetal) pulmonary circulation, tl

Recent studies have identified NO or an NO-containing substance as the endothelium-derived relaxing factor that plays an important role in regulating vascular tone and structure.7, 12-14 Although mechanisms contributing to its pathogenesis and pathophysiology are poorly understood, recent studies suggest that pulmonary arteries in patients with pulmonary hypertension have diminished endogenous endothelium-derived relaxing factor-NO activity. 15 On the basis of the potent vasodilator properties of inhaled N O in our patient and in the previously published report of adults with primary pulmonary hypertension, 4 smooth muscle cell responsiveness to inhaled NO appears to be preserved. We conclude that low doses of inhaled NO cause selective and sustained pulmonary vasodilation without systemic hypotension or tachyphylaxis. Because of the high mortality rates and limited therapies for primary or unexplained

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pulmonary hypertension, future studies of the safety and efficacy of long-term treatment with N O are warranted. REFERENCES I. Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension: a national prospective study. Ann Intern Med 1987;107:216-23. 2. Rich S, Brundage BH. High-dose calcium channel-blocking therapy for primary pulmonary hypertension: evidence for long-term reduction in pulmonary arterial pressure and regression of right ventricular hypertrophy. Circulation 1987; 76:135-41. 3. Weir EK. Acute vasodilator testing and pharmacological treatment of primary pulmonary hypertension. In: Fisbman AP, ed. Pulmonary circulation: normal and abnormal. Philadelphia: University of Pennsylvania Press, 1990:485-99. 4. Pepke-Zaba J, Higenbottam TW, Dinh-Xuan AT, Stone D, Wallwork J. Inhaled nitric oxide as a cause of selective pulmonary vasodilation in pulmonary hypertension. Lancet 1991;338:173-4. 5. Roberts JD, Polaner DM, Lang P, Zapol WM. Inhaled nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 1992;340:818-9. 6. Kinsella JP, Neish SR, Shaffer E, Abman SH. Low-dose inhalational nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 1992;340:819-20. 7. Moncada SA, Palmer RMJ, Higgs EA. NO: physiology, pathophysiology and pharmacology. Pharmacol Rev 1991;43:

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8. Meyer M, Piiper J. Nitric oxide (NO), a new test gas for study of alveolar-capillary diffusion. Eur Respir J 1989;2:494-6. 9. Frostell C, Fratacci M, Wain JC, Jones R, Zapol WM. Inhaled nitric oxide: a selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction. Circulation 1991;83:203847. 10. Frataci MD, Frostell CG, Chen TY, Wain JC, Robinson DR, Zapol WM. Inhaled NO: a selective pulmonary vasodilator of heparin-protatnine vasoconstriction in sheep. Anesthesiology 1991;75:990-9. 11. Kinsella JP, McQueston JA, Rosenberg AA, Abman SH. Hemodynamic effects of exogenous nitric oxide in ovine transitional pulmonary circulation. Am J Physiol (Heart Circ Physiol) 1992;32:H875-80. 12. Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature (London) 1980;288:373-6. 13. Palmer RMJ, Ferrige AG, Moncada SA. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987;327:524-6. 14. Ignarro L J, Buga GM, Wood KS, Byrns RE, Chaudhuri G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Set USA 1987;84:9265-9. 15. Dinh Xuan AT, Higenbottam TW, Clelland C, Pepke-Zaba J, Cremona G, Wallwork J. Impairment of pulmonary endothelium-dependent relaxation in patients with Eisenmenger's syndrome. Br J Pharmacol 1990;99:9-10.

109-42.

Pharmacokinetics of dapsone in children Mark Mirochnick, MD, Marian Michae]s, MD, Diana Clarke, PharmD, Anne Brefia, BS, Anne Marie Regan, RN, MS, and Stephen Pelton, MD From the Department of Pediatrics, Boston City Hospital and Boston University School of Medicine, Boston, Massachusetts, and the Division of Infectious Diseases, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania

We studied dapsone pharmacokinetics in eight children with compromised immune function who were receiving three different preparations. Peak serum concentration was less than 0.25 pg/ml after doses of an extemporaneous liquid preparation but ranged from 0.72 to 1.33 pg/ml after initial tablet or proprietary liquid doses and 1.48 to 2.48 pg/ml during long-term proprielary liquid administration. Elimination followed first-order kinetics; the mean elimination halflife was 15.1 hours. (J PEDIATR1993;122:806-9)

Supported in pa0rt by grant No. AI27557 from the National Institutes of Health, Bethesda, Md. Submitted for publication Sept. 17, 1992; accepted Dec. 9, 1992. Reprint requests: Mark Mirochnick, MD, Maternity 2, Boston City Hospital, 818 Harrison Ave., Boston, MA 02118. Copyright 9 1993 by Mosby-Year Book, Inc. 0022-3476/93/$1.00 + .10 9/26/44791

Children with compromised immune function are at high risk for the development of Pneumoo,stis carinii pneumonia. Trimethoprim-sulfamethoxazole, the agent of first choice for prophylaxis against PCP, is not tolerated by up to 15% of children infected with the human immunodeficiency virus, primarily because of the development of rashes and neutropenia. 1,2 The use of pentamidine in small